This proposal evaluates the hypothesis that calcium dynamics are altered in aging hippocampal and perirhinal neurons. The calcium hypothesis for aging and dementia posits that dysregulation of Ca2+ homeostasis contributes to neuropathological changes associated with aging-related illnesses such as Alzheimer's Disease (AD). Aging animals, including humans, are impaired in a variety of learning tasks tat depend upon these temporal lobe regions. Perirhinal and hippocampal neurons of patients with Alzheimer's disease contain neurofibrillar tangles, and these brain region are among the first to exhibit age-related changes. Previous intracellular recording data demonstrated increased Ca2+ dependent K+ conductances and prolonged Ca2+ action potentials in aged CA1, but the biophysical characteristics of aged perirhinal cortical neurons have yet to be studied. Confocal scanning laser microscopy (CSLM) will be combined with simultaneous whole-cell recording to study somatic and dendritic Ca2+ dynamics in young and aged perirhinal and hippocampal CA1 pyramidal neurons in vitro. Video enhanced, differential interference contrast microscopy will be combined with CLSM to allow recordings from visually identified neurons. Pharmacological studies will evaluate the effects of cognitive enhancers on calcium dynamics in aging neurons. Advancing age and rising health care costs for persons suffering from aging-related illnesses such as AD clearly motivate research that could aid in understanding the cellular neurobiological processes that occur in the aged brain and that may lead to the development of treatments that may ultimately prove useful for cutting the cost of health care for an increasingly aging U.S. world population.